Skin whiteners containing hydroxytetronic acid

ABSTRACT

Skin whitening compositions contain α-hydroxytetronic acid or a α-hydroxytetronic derivative, and, in some cases, hydroquinone, an α-hydroxy acid such as glycolic acid, and a fatty acid ester of ascorbic acid such as ascorbyl palmitate.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0001] Not Applicable

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to the use of hydroxytetronic acid and/orhydroxytetronic acid derivatives alone, or in combination with otheringredients such as hydroquinone, glycolic acid, and/or ascorbylpalmitate, in compositions that whiten skin, and methods for using thecompositions.

[0004] 2. Description of Related Art

[0005] A variety of dermatological compositions have been suggested forskin whitening to improve the appearance of hyperpigmentary skinconditions such as that observed as freckles, melasma, café au lait andliver spots spots, and lesions observed in Addison's disease,hemochromatosis, vitiligo, piebald-ism, phenylketonuria, and the like,and/or for cosmetic purposes. Skin color is primarily determined by theamount of melanin present in epidermal cells, so many modern skinbleaching compositions either destroy melanin (typically by destroyingor disrupting melanin granules) or inhibit its formation (often byinhibiting tyrosinase, a melanin biosynthetic enzyme, or melanocyteactivity), or both. Many of these contain harsh chemicals such asperoxides, acids or formaldehyde, or thiolated materials such asglutathione, cysteine, mercaptosuccinic acid, mercaptodextran, andmercapto-ethanol, which have an objectionable odor that makes productscontaining them undesirable to a consumer (discussed in U.S. Pat. No.5,980,904 to Leverett and Dornoff, 5,747,006 to Dornoff, et al., and6,077,503 to Dornoff; these and subsequent references are herebyincorporated herein in their entireties by reference).

[0006] Less stringent therapies have other disadvantages. The onlytreatment for hyperpigmentation that is approved in the United Statesfor use by consumers without a prescription, for example, is the topicalapplication of hydroquinone, which acts by suppressing melanocyteactivity. Hydroquinone is oxidized by air, light, and tyrosinase itself,however, which adversely effects the shelf life of preparationscontaining it and its bioavailability upon application. Hydroquinone cancause burning, redness, sensitization and irritation in some persons,particularly after application of quantities sufficient to cause skinbleaching as it requires prolonged treatment before results arenoticeable, and its oxidized products have been implicated in skinirritation and pigmentation rebound (U.S. Pat. No. 6,068,834 to Kvalnes,et al.). Topical retinoids and topical corticosteroids have beensuggested as hypopigmenting agents, as have laser treatment and chemicalpeels, but these fall short of desirable responses. A new combinationtherapy recently suggested combines tretinoin and fluocinolone withhydroquinone (Willis, I., Skin & Aging Supp., Nov. 2000, 17-21). Kojicacid and arbutin have also been suggested, but these are marginaltyrosinase inhibitors and are not very bioavailable and thus havedisappointing efficacy.

[0007] Other pleasanter compositions recently suggested employ naturalmaterials, which have in some cases been used for centuries in Asia orEurope to bleach skin and skin areas, or enhance the appearance of fairskin. These include the use of lemon, orange, cucumber, ginko, carob,rose fruit, geraniuim herb, cinnamon, sweet marjoram, rosemary, clove,mulberry, licorice, bearberry, and acerola cherry extracts (ibid.). Thevariability of active ingredients in these natural products sometimeslimits their usefulness, particularly as skin type, color, age, andcondition of vary greatly in different subjects, and make suggesteddosages and regimens difficult to fashion. And other ingredients in themixtures can cause allergic reactions in sensitive persons.

[0008] It would be desirable to have alternative preparations, and/orones that improve the efficacy of presently known skin whitening agents.

BRIEF SUMMARY OF THE INVENTION

[0009] It is an objective of the invention to provide new compositionsfor whitening skin and methods for their use. It is a further objectiveto provide compositions that can be used to enhance known skin whiteningcompositions and treatments.

[0010] These objectives are achieved by the present invention, whichprovides methods and compositions for whitening skin through the topicalapplication of α-hydroxytetronic acid and/or 60 -hydroxytetronicderivatives, in a preparation that typically includes a dermatologicallyacceptable carrier. In many embodiments, the α-hydroxytetronic activeingredient is applied to skin in combination with at least one adjunctingredient such as hydroquinone, an α-hydroxy acid such as glycolicacid, and a fatty acid ester of ascorbic acid such as ascorbylpalmitate. Some preferred embodiments contain from about 0.5% to about25% by weight α-hydroxytetronic acid and/or hydroxytetronic acidderivatives alone, or in combination with hydroquinone, glycolic acidand/or ascorbyl palmitate.

BRIEF DESCRIPTION OF THE INVENTION

[0011] This invention is based upon the finding that α-hydroxytetronicacid, alone or in combination with hydroquinone, provides significantbleaching when applied to the skin, without undesirable side effects.

[0012] In the practice of the invention, a composition containing aneffective amount of α-hydroxytetronic acid active ingredient, i.e.,α-hydroxytetronic acid, a derivative, or mixtures thereof, is applied toskin to whiten it. By “whitening” is meant the visually apparentreduction in skin pigmentation observed qualitatively and sometimesmeasured using an assay such as Melanoderm in vitro assays that quantifychanges in melanin formation in cultured mammalian epidermal cells.Alpha-hydroxytetronic acid (sometimes called 2-hydroxytetronic acid) maybe thought of as ascorbic acid without a side chain; the enol form,3,4-dihydroxy-2-(5H) furnanone, has the formula

[0013] Alpha-hydroxytetronic acid derivatives include, but are notlimited to, acylated α-hydroxytetronic acid derivatives, particularly C₁to C₆ (hereinafter referred to as “lower”) straight- or branched-chainalkyl esters; hyroxytetronic acid salts, particularly sodium, potassium,and magnesium salts (hereinafter collectively referred to as“physiologically acceptable salts”); alkyl derivatives, particularlylower, or C₁ to C₈, alkyls, i.e., derivatives having a methyl-, ethyl-,and propyl- group in the γ- (4-) position (sometimes called,respectively, tetrinic, pentinic, and hexinic acid), and their estersand salts, particularly lower alkyl esters and their physiologicallyacceptable salts); cycloaliphatic derivatives, i.e., derivatives havingalkyl hydrocarbon side chains which are closed to form a ring structure,particularly those having a hydrocarbon ring structure containing from 3to 6 carbon atoms attached to the γ- (4-) position; alkoxy derivatives,particularly those having a lower alkyl group attached to the moleculein the α-(2-), β- 3-), or γ-(4-) position by oxygen such as methoxy-,ethoxy-, propoxy-, and isopropoxy- derivatives, and the like; arylderivatives, particularly those having a phenyl, benzyl, tolyl, orphenethyl group in the γ-(4-) position, and substituted aryls, notablyhalogenated derivatives such as those having a chlorophenyl ordichlorophenyl group attached to the γ-(4-) position; their lower alkylessters and physiologically acceptable salts; and mixtures thereof. Forconvenience, as used herein, the term “hydroxytetronic acid” includesα-hydroxytetronic acid itself, alone or in combination with knownderivatives, esters, salts, and the like. Specifically encompassed areoptical isomers and racemic mixtures, and natural vitamin C mixturesenriched with α-hydroxytetronic acid and/or its derivatives.

[0014] Typical compositions of the invention contain from about 0.5% toabout 25% by weight, more narrowly from about 2% to about 15% by weight,and even more narrowly from about 3% to about 10% by weight,α-hydroxytetronic acid and/or a derivative thereof. Lower concentrationsmay be employed for less pronounced hyperpigmentation conditions and insunscreens and sunblocks used after skin whitening treatment (more fullydiscussed below), and higher concentrations may be employed with moreacute pigmentation conditions. Suggested ranges also depend upon anyadjunct ingredients employed in the compositions (more fully discussedbelow) and the user's coloring and skin type as well as the extent ofseverity of the hyperpigmentation problem. Some embodiments contain fromabout 1% to 10%, more narrowly from about 2% to about 5%, even morenarrowly from about 3% to about 4% by weight hydroxytetronic acid;others contain from about 7% to about 25%, more narrowly from about 10%to about 15%, by weight hydroxytetronic acid. As a practical matter,however, to avoid the need for repeated application, it is desirablethat the topically applied composition be formulated to contain at leastabout 3 to 5% by weight hydroxytetronic acid, and many embodimentscontain about 10% or higher.

[0015] As summarized above, some whitening compositions of the inventioncontain at least one other adjunct ingredient in addition tohydroxytetronic acid. Adjunct ingredients include, but are not limitedto, hydroquinone, α-hydroxy acids, and fatty acid esters of ascorbicacid. Many embodiments employ more than one adjunct ingredient.Especially preferred bleaching compositions contain hydroquinone(sometimes also called p-dihydroxybenzene or 1,4 benzenediol) inaddition to the hydroxytetronic active ingredient. Typical hydroquinoneconcentrations range from about 0.25% to about 25% by weight, morenarrowly from about 1% to about 5%, and even more narrowly from about 2%to about 4% by weight.

[0016] As used herein, the term “α-hydroxy acid” has reference to andencompasses the general class of organic compounds containing at leastone hydroxy group and at least one carboxyl group, and wherein at leastone hydroxyl group is located on the α-carbon atom. Typically, thecompounds are organic acids having at least one carboxylic acid groupand at least one hydroxyl group on the α-carbon atom, and may containother functional groups including additional hydroxyl and carboxylicacid moieties. Preferred α-hydroxy acids and/or α-hydroxy acidderivatives are those which are less bulky structurally, typicallyhaving a one- to three-carbon backbone, so that they penetrate the skinwell such as those set out in U.S. Pat. No. 5,965,618 at column 6 lines4 to 29. Where employed, glycolic and/or lactic acid or theirderivatives are preferred; glycolic acid is especially efficacious.Lactic acid was suggested as a skin-whitening agent in U.S. Pat. No.5,262,153 to Mashima, et al. Typical hydroxy acid concentrations rangefrom about 1% to about 25% by weight, more narrowly from about 2% toabout 15%, and even more narrowly from about 3% to 10% by weight. Aswith the hydroxytetronic acid ingredient, higher concentrations may beemployed for more acute conditions. In some embodiments, for example,from about 8% to 12% may be employed; in others, ranges of from about 3%to about 7% by weight are sufficient. One efficacious composition of theinvention contains about 10% hydroxytetronic acid, about 10% glycolicacid, and about 4% hydroquinone.

[0017] Fat-soluble fatty acid esters of ascorbic acid (vitamin C) areemployed as alternate or additional adjunct ingredients in otherembodiments, alone or in combination with hydroquinone or α-hydroxyacids. The more oxidation-resistant saturated fatty acid esters ofascorbic acid are preferred, including, but not limited to, ascorbyllaurate, ascorbyl myristate, ascorbyl palmitate, ascorbyl stearate, andascorbyl behenate. Ascorbyl palmitate is used in one embodiment. Asdenoted herein, where fatty acid esters are described, e.g., ascorbylstearate, compositions having predominantly that ester, e.g.,predominantly stearate, are included. The esters may be prepared usinghydrogenated oils or fats, or fractions thereof, and contain smallamounts of another ester. Ascorbyl stearate prepared using canola, forexample, commonly contain about 4% ascorbyl palmitate. It is anadvantage of the invention that where fatty acid esters of ascorbic acidare employed as an adjunct ingredient, they help provide emollientproperties to the composition. Typical concentration ranges of ascorbylpalmitate vary from about 0.25% to about 10%, more narrowly from about2% to about 8%, and even more narrowly from about 3% to about 5% byweight.

[0018] However, only effective amounts of active ingredient(s) areneeded to whiten skin, so generally topical application to skin sites isaccomplished in association with a carrier, and particularly one inwhich the active ingredient is soluble per se or is effectivelysolubilized (e.g., as an emulsion or microemulsion). Where employed, thecarrier is inert in the sense of not bringing about a deactivation oroxidation of active or adjunct ingredient(s), and in the sense of notbringing about any adverse effect on the skin areas to which it isapplied. In one preferred practice of the invention, hydroxytetronicacids are applied in admixture with a dermatologically acceptablecarrier or vehicle (e.g., as a lotion, cream, ointment, soap, stick, orthe like) so as to facilitate topical application and, in some cases,provide additional beneficial effects as might be brought about, e.g.,by moisturizing of the affected skin or mucosal areas. While the carrierfor dermatological compositions can consist of a relatively simplesolvent or dispersant such as water, it is generally preferred that thecarrier comprise a composition more conducive to topical application,and particularly one which will form a film or layer on the skin towhich it is applied so as to localize the application and provide someresistance to washing off by immersion in water or by perspirationand/or aid in the percutaneous delivery of the active agent. Manypreparations are known in the art, and include lotions containing oilsand/or alcohols and emollients such as olive oil, hydrocarbon oils andwaxes, silicone oils, other vegetable, animal or marine fats or oils,glyceride derivatives, fatty acids or fatty acid esters or alcohols oralcohol ethers, lecithin, lanolin and derivatives, polyhydric alcoholsor esters, wax esters, sterols, phospholipids and the like, andgenerally also emulsifiers (nonionic, cationic or anionic), althoughsome of the emollients inherently possess emulsifying properties. Thesesame general ingredients can be formulated into a cream rather than alotion, or into gels, or into solid sticks by utilization of differentproportions of the ingredients and/or by inclusion of thickening agentssuch as gums or other forms of hydrophilic colloids. One preferredembodiment is an oil-in-water cream. Such compositions are referred toherein as dermally, dermatologically, or pharmaceutically acceptablecarriers.

[0019] Suitable carriers include water, alcohols, oils and the like,chosen for their ability to dissolve or disperse ingredients used in thetreatment. In some embodiments, active and/or adjunct ingredients areadded to a sunscreen or sunblock formulations so that topicalapplication has the further advantage of preventing repigmentationduring and/or after treatment. Preferred formulae of this type are SPF15 or higher. Many of these preferred embodiments contain titaniumdioxide or zinc oxide which additionally soothe and lubricate the skinand help minimize side effects in sensitive skin and with formulationscontaining high concentrations of bleaching ingredients.

[0020] Generally in the practice of methods of the invention, thecomposition is topically applied to darkened skin areas in apredetermined or as-needed regimen either at intervals by application ofa lotion or the like, it generally being the case that graduallightening is noted with each successive application. Insofar as hasbeen determined based upon clinical studies to date, no adverse sideeffects are encountered. It is an advantage of the invention that it canbe used to augment other skin lightening treatments including, but notlimited to, those discussed above such as topical administration ofhydroquinone, hydroquinone and glycolic acid, and kojic acid.

[0021] The above description is for the purpose of teaching the personof ordinary skill in the art how to practice the present invention, andit is not intended to detail all those obvious modifications andvariations of it which will become apparent to the skilled worker uponreading the description. It is intended, however, that all such obviousmodifications and variations be included within the scope of the presentinvention, which is defined by the following claims. The claims areintended to cover the claimed components and steps in any sequence whichis effective to meet the objectives there intended, unless the contextspecifically indicates the contrary.

1. A method for whitening skin comprising topically administering to theskin an effective amount of a composition containing from about 0.5% toabout 25% by weight of an active ingredient selected from the groupconsisting of α-hydroxytetronic acid; α-hydroxytetronic acid substitutedin the γ-position with a C₁ to C₈ alkyl, C₃ to C₆ cycloaliphatic,phenyl, chlorophenyl, dichlorophenyl, tolyl, or phenethyl group; loweralkoxy derivatives; their lower alkyl esters and physiologicallyacceptable salts; and mixtures thereof.
 2. A method according to claim 1wherein the composition contains from about 2% to about 15% by weightactive ingredient.
 3. A method according to claim 1 wherein thecomposition contains from about 3% to about 10% active ingredient.
 4. Amethod according to claim 1 wherein the active ingredient isα-hydroxytetronic acid.
 5. A method according to claim 1 wherein thecomposition further comprises at least one adjunct ingredient selectedfrom the group consisting of hydroquinone, an α-hydroxy acid, a fattyacid ester of ascorbic acid, and mixtures thereof.
 6. A method accordingto claim 5 wherein one adjunct ingredient is hydroquinone.
 7. A methodaccording to claim 5 wherein one adjunct ingredient is glycolic acid. 8.A method according to claim 5 wherein one adjunct ingredient is ascorbylpalmitate.
 9. A method for whitening skin comprising applying to theskin a composition containing an effective amount of α-hydroxytetronicacid and at least one adjunct ingredient selected from the groupconsisting of hydroquinone, an α-hydroxy acid, and a fatty acid ester ofascorbic acid.
 10. A method according to claim 9 wherein an adjunctingredient is hydroquinone.
 11. A method according to claim 9 wherein anadjunct ingredient is glycolic acid, ascorbyl palmitate, or mixturesthereof.
 12. A method according to claim 9 wherein the compositioncontains from about 0.5% to about 25% by weight α-hydroxytetronic acidand from about 0.25% to about 25% by weight adjunct ingredient.
 13. Atopical composition useful for whitening skin comprising adermatologically acceptable carrier and (a) from about 0.5% to about 25%by weight of an active ingredient selected from the group consisting ofα-hydroxytetronic acid; γ-hydroxytetronic acid substituted in theγ-position with a C₁ to C₈ alkyl, C₃ to C₆ cycloaliphatic, phenyl,chlorophenyl, dichlorophenyl, tolyl, or phenethyl group; lower alkoxyderivatives; their lower alkyl esters and physiologically acceptablesalts; and mixtures thereof; and (b) from about 0.25% to about 25% byweight of at least one adjunct ingredient selected from the groupconsisting of hydroquinone, an α-hydroxy acid, and a fatty acid ester ofascorbic acid.
 14. A composition according to claim 13 wherein theactive ingredient is α-hydroxytetronic acid and the adjunct ingredientis hydroquinone, glycolic acid, ascorbyl palmitate, or mixtures thereof.15. A composition according to claim 14 which comprises from about 2% toabout 15% by weight hydroxytetronic acid.
 16. A composition according toclaim 14 wherein the composition comprises from about 0.25% to about 25%hydroquinone.
 17. A composition according to claim 16 which comprisesfrom about 1% to about 5% hydroquinone.
 18. A composition according toclaim 14 wherein the composition comprises from about 8% to about 12% byweight glycolic acid.
 19. A composition according to claim 14 whereinthe composition comprises from about 0.25% to about 10% by weightascorbyl palmitate.
 20. A composition according to claim 13 whichcomprises about 10% by weight α-hydroxytetronic acid, about 10% byweight glycolic acid, and about 4% by weight hydroquinone.